DESCRIPTION (Applicant's Description): The surface immunoglobulin complex (sIg) on B-cells and various types of Fc receptors transduce signals through the interaction of cytoplasmic tail immunoreceptor tyrosine based activation motifs (ITAMs) with SRC family kinases and the SYK tyrosine kinase. Recent work by several investigators has demonstrated that activation of these receptors induces SRC family kinases and SYK to physically interact with the CBL proto-oncogene to form CBL/kinase complexes. In addition, the preliminary data of the applicant indicated that SRC family kinases and SYK act cooperatively in generating Fc receptor induced CBL tyrosine phosphorylation. CBL is an intriguing protein because it is rapidly tyrosine phosphorylated in multiple different tyrosine phosphorylation mediated signaling pathways, suggesting that it has a general role in the regulation of tyrosine kinase signaling. Furthermore, a transforming mutation of CBL is constitutively tyrosine phosphorylated, suggesting that whatever function CBL subserves is regulated by its own tyrosine phosphorylation. In order to gain a clearer understanding of CBL function, this proposal will accomplish three distinct aims: Aim 1 will identify CBL tyrosine phosphorylation sites induced by receptor activation and by a transforming mutation of CBL to determine whether these processes access the same or similar CBL functions. In addition, the tyrosine kinases responsible for the receptor-induced phosphorylation of these sites will be determined. Aim 2 will attempt to identify signaling pathways which lie upstream or downstream of CBL, and to determine whether CBL acts negatively or positively in these pathways using vaccinia virus driven expression of CBL and various mutations in Fc receptor and sIg signaling systems. The experiments proposed in this aim will focus on evaluating the ability of CBL mutants to interact with putative upstream and downstream CBL effectors, examining the effects of overexpression of CBL mutants on Fc receptor or sIg-mediated events known to involve CBL interacting proteins, and attempting to correlate specific CBL/effector molecule interactions with effects on these signaling events. Aim 3 will use the information from Aim 1 to define how tyrosine phosphorylation allows CBL to accomplish signaling tasks identified in Aim 2, and will also evaluate the role of phosphorylation sites identified in Aim 1 in CBL's transforming capability. Together, the data derived from these aims will identify signal transduction processes in which CBL is involved, and provide mechanistic explanations for how CBL participates in them.